The goal of this proposed research is to determine whether differences in the expression of epigenetic related biomarkers are present in lymphocytes of people with genetic high risk and/or prodromal symptoms of schizophrenia (HRSK subjects) as previously found in lymphocytes of chronic schizophrenia (SZ) patients. We will also assess whether the presence of these biomarkers predicts which HRSK subjects will progressively develop more psychotic symptoms over a two year period and who will convert from HRSK status to first episode schizophrenia or another diagnosable psychotic disorder. Investigators on this proposal, have been collaborating with a group of investigators in Hunan, China for several years (Wu et al., 2008; 2012). The China group is currently conducting a multi-center study supported by the Chinese Ministry of Health that involves 5000 HRSK and 2000 control subjects. The research we are proposing would be an addendum to this larger study. DNA methylation and demethylation are key epigenetic components involved in orchestrating transcription of specific genes in post mitotic neurons (Guidotti et al., 2011). It has been suggested that the DNA methylation/demethylation process is perturbed in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP), and autism. We have shown that abnormalities in some of these epigenetic marks in the brain of SZ patients are also present in their lymphocytes. Lymphocytes of SZ patients have higher DNMT1 mRNA expression than non-psychotic controls (Zhubi et al 2009), higher levels of other methylating and demethylating enzymes (growth arrest and DNA damage-inducible protein [GADD45] and ten-eleven translocation protein [TET]), and lower levels of glucocorticoid receptor and GAD67 mRNA (preliminary data). If differences in these potential epigenetic biomarkers can be confirmed in lymphocytes of HRSK subjects, some of the underlying biochemical developmental pathology leading to SZ might be uncovered. This result could provide epigenetic biomarkers useful in predicting which HRSK subjects are more likely to develop full symptoms of SZ or a related psychosis. Identifying potential biomarkers would have implications for prognosis and identifying patients who would be most likely to benefit from intensive early intervention and specialized treatment. This background leads us to pursue three Specific Aims for the current proposed study: AIM1: Measure the expression level of DNA methylation related genes in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 2: Determine whether epigenetic chromatin status and the expression of SZ candidate genes is regulated by the binding of proteins that are constituents of the DNA- methylation/demethylation pathways in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 3 Determine whether HRSK subjects who also have epigenetic lymphocyte abnormalities at baseline are more likely to progress to more severe psychotic-like symptoms or convert to diagnosable psychotic status during a two year follow up. This proposed research is potentially a major step toward the identification of objective biomarkers capable of predicting conversion to psychosis in HRSK subjects.